Walking duration and pain-free walking both improved significantly in patients with claudication after treatment with the ACE inhibitor ramipril, a randomized trial showed.

The average pain-free walking time increased by more than 60% and maximum walking time more than doubled after 6 months of treatment with the ACE inhibitor.

Almost all secondary outcomes improved significantly with ramipril versus placebo, including ankle-brachial index (ABI), an impairment scale specific to peripheral arterial disease (PAD), and functional aspects of health-related quality of life, an Australian research team reported in the Feb. 6 issue of JAMA.

"ACE inhibition is not specifically recommended for the relief of intermittent claudication," Anna A. Ahimastos, PhD, of the Baker Heart and Diabetes Institute in Melbourne, Australia, and co-authors wrote in conclusion. "To our knowledge, this is the first adequately powered randomized trial demonstrating that treatment with ramipril is associated with improved treadmill walking performance in patients with PAD."

About a third of patients with PAD have intermittent claudication, characterized by pain during walking that is relieved by rest. Intermittent claudication can substantially impair ambulatory function, leading to disability and severe lifestyle limitations.

Treatment for PAD focuses on reducing cardiovascular risk and improving function and quality of life. Medical therapy usually has no more than a modest effect on walking distance. For example, the only drugs approved for PAD in the U.S. (pentoxifylline and cilostazol) increase walking distance by 15% to 25%, the authors noted.

The trial involved 212 patients with symptomatic PAD. The patients were randomized to daily ramipril or matching placebo and followed for 24 weeks. Patients underwent treadmill assessments before randomization and at the end of the trial. The primary endpoints were change in duration of pain-free walking and in maximum walking time.

Patient-reported symptoms and functional status were assessed by the Walking Impairment Questionnaire (WIQ), and health-related quality of life was assessed by the SF-36 survey.

Baseline characteristics did not differ significantly between treatment groups. The patients had a mean age of 65 to 66 and a mean body mass index of 25 to 26. Half of the patients had hypertension, about 28% had never smoked, and about a fourth of the patients had diabetes.

The baseline mean pain-free walking time was 140.3 seconds in the ramipril arm and 144.2 seconds in the placebo group. Maximum walking time averaged 233.6 and 238.4 seconds in the ramipril and placebo groups, respectively, and limiting-leg ABI at rest of 0.57 and 0.55 in the respective groups.

Previous studies and a meta-analysis yielded inconsistent results for evaluations of ACE inhibitor therapy in PAD, Mary McGrae McDermott, MD, commented in an accompanying editorial. However, the trials involved few patients, employed different ACE inhibitors, and several were conducted in the 1990s, raising questions about their relevance to management of PAD in contemporary populations.

"Given the paucity of effective therapies for treating functional limitation in PAD and recent randomized controlled trials that have failed to demonstrate improved walking performance in response to novel medical therapies in PAD, the magnitude of improvement with ramipril in the study by Ahimastos et al. is particularly notable," wrote McDermott, of Northwestern University in Chicago.

However, McDermott raised several issues warranting a cautious interpretation of the results: possible inherent differences in patient populations outside of Australia, potential differences in the activity of various ACE inhibitors, a relatively minor improvement in the placebo group as compared with previous studies, and use of exclusion criteria that might limit the generalizability of the findings.

The study was supported by the National Heart Foundation of Australia, the National Health and Medical Research Council of Australia, and the Operational Infrastructure Support Program of the Victorian State Government.

Ahimastos had no relevant disclosures. Co-authors disclosed relationships with sanofi-aventis and Novartis.

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